Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer
Sagar R. Shah,
Justin M. David,
Nathaniel D. Tippens,
Ahmed Mohyeldin,
Juan C. Martinez-Gutierrez,
Sara Ganaha,
Paula Schiapparelli,
Duane H. Hamilton,
Claudia Palena,
Andre Levchenko,
Alfredo Quiñones-Hinojosa
Affiliations
Sagar R. Shah
Department of Neurologic Surgery, The Mayo Clinic, Jacksonville, FL, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Justin M. David
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Nathaniel D. Tippens
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA
Ahmed Mohyeldin
Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
Juan C. Martinez-Gutierrez
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Sara Ganaha
Department of Neurologic Surgery, The Mayo Clinic, Jacksonville, FL, USA
Paula Schiapparelli
Department of Neurologic Surgery, The Mayo Clinic, Jacksonville, FL, USA
Duane H. Hamilton
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Claudia Palena
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Andre Levchenko
Department of Biomedical Engineering and Systems Biology Institute, Yale University, New Haven, CT, USA; Corresponding author
Alfredo Quiñones-Hinojosa
Department of Neurologic Surgery, The Mayo Clinic, Jacksonville, FL, USA; Corresponding author
Summary: Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors. : Malignant neoplasms exhibit uninhibited and dysregulated growth coupled with acquisition of stem-like properties that are integral to the development and progression of disease. Shah et al. demonstrate a critical role of brachyury in regulating stemness and growth by activating YAP through direct transcriptional and post-transcriptional mechanisms in various cancers. Keywords: brachyury, YAP, chordoma, stremness, growth, glioblastoma, lung carcinoma